PDF(Pubmed)
Abstract：
Targeted therapy for lung squamous cell carcinoma (LUSC) remains a challenge due to the lack of robust targets. Here, we identified MECOM as a candidate of therapeutic target for LUSC by screening 38 genes that were commonly amplified in three pairs of primary tumors and patient-derived xenografts (PDXs) using a clustered regularly interspaced short palindromic repeats (CRISPR)-mediated approach. High MECOM expression levels were associated with poor prognosis. Forced expression of MECOM in LUSC cell lines promoted cancer stem cell (CSC) properties, and its knockout inhibited CSC phenotypes. Furthermore, systemic delivery of CRISPR-mediated MECOM depletion cassette using adenovirus with an adaptor, which is composed of a single-chain fragment variable (scFv) against epithelial cell adhesion molecules (EpCAM) fused to the ectodomain of coxsackievirus and adenovirus receptor, and a protector, which consists of the scFv connected to the hexon symmetry of the adenovirus, could specifically target subcutaneous and orthotopic LUSC and retard tumor growth. This study could provide a novel therapeutic strategy for LUSC with high efficacy and specificity.
摘要：
由于缺乏强大的靶标，肺鳞状细胞癌（LUSC）的靶向治疗仍然是一个挑战。这里,我们通过使用成簇的规则间隔短回文重复序列(CRISPR)介导的方法筛选3对原发性肿瘤和患者来源的异种移植物(PDX)中通常扩增的38个基因,将MECOM确定为LUSC的候选治疗靶点.高MECOM表达水平与不良预后相关。MECOM在LUSC细胞系中的强制表达促进了肿瘤干细胞（CSC）的特性，其敲除抑制CSC表型。此外，使用带有衔接子的腺病毒全身递送CRISPR介导的MECOM耗尽盒，它由针对上皮细胞粘附分子（EpCAM）的单链片段变量（scFv）与柯萨奇病毒和腺病毒受体的胞外域融合组成，一个保护者,它由与腺病毒的六邻体对称相连的scFv组成，可以特异性靶向皮下和原位LUSC并延缓肿瘤生长。这项研究可以为LUSC提供一种新的治疗策略，具有高疗效和特异性。
